CN117164590A - Fused pyrimidine derivative and application thereof - Google Patents

Fused pyrimidine derivative and application thereof Download PDF

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Publication number
CN117164590A
CN117164590A CN202210578200.XA CN202210578200A CN117164590A CN 117164590 A CN117164590 A CN 117164590A CN 202210578200 A CN202210578200 A CN 202210578200A CN 117164590 A CN117164590 A CN 117164590A
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pyrimidine
substituted
dimethyl
methylmorpholin
dihydro
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赵燕芳
侯云雷
齐银良
王昆
龙彬
肖明霏
杨德孝
佟明辉
西治国
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Suzhou Shengsu New Drug Development Co ltd
Shenyang Pharmaceutical University
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Suzhou Shengsu New Drug Development Co ltd
Shenyang Pharmaceutical University
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Priority to PCT/CN2023/106083 priority patent/WO2023227139A1/en
Publication of CN117164590A publication Critical patent/CN117164590A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a novel condensed pyrimidine compound shown in a general formula I or stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, and a preparation method and application thereof 1 、R 2 A, Y, L, n have the meanings given in the description. The invention also relates to application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicaments for treating diseases caused by abnormal high expression of ATR, in particular to preparation of medicaments for treating the diseases caused by abnormal high expression of ATRThe use in medicaments for the treatment and/or prevention of hyperproliferative diseases, including but not limited to gastric cancer, liver cancer, colorectal cancer, ovarian cancer, pancreatic cancer and the like.

Description

Fused pyrimidine derivative and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a fused pyrimidine derivative and application thereof.
Background
Ataxia telangiectasia mutated and Rad3 related kinase (ATR) is a serine/threonine protein kinase that forms part of the DNA Damage Response (DDR) with ATM and DNA-PK, coordinating the response of cells to DNA damage, stress and cell cycle disturbances. ATR is critical for viability of replicating cells that respond to accumulation of Single Strand Breaks (SSBs) in DNA (e.g., stagnant replication forks) and massive DNA damage (e.g., damage from chemotherapeutics and uv radiation). The sensitivity of tumor cells to chemotherapeutic agents has been shown to be caused by genetic modulation of ATR activity.
ATR kinase is responsible for initiating the response and repair of cells to genomic instability, and once DNA damage and replication cross stress are felt, they are rapidly activated, directly phosphorylating more than 1000 important substrates (including the oncogene p53 encoded protein, cell cycle regulatory protein, etc.) within the cell, globally regulating the stability of the genome. Cancer cells typically have high levels of oncogene-induced replicative stress, which are more dependent on ATR kinase. ATR kinase inhibitors can interfere with DNA repair, promote cancer cell DNA to be errant and not repaired, and ultimately promote tumor cell apoptosis. Studies have shown that upregulation of ATR expression, such as liver, stomach, ovarian, pancreatic, gastric, etc., is observed in a variety of tumor tissues, and that patients with high levels of ATR are often accompanied by low survival rates. ATR is seen as an important tumor therapeutic target, and ATR inhibitors are also important antitumor drugs.
Compounds currently in preclinical and clinical research stages include CeraLasertib (AZD-6738), berzosertib (VX-970, M6620), BAY1895344, M4344, etc., wherein AZD-6738 and VX-970 are currently in clinical stage II, and BAY-1895344 and M4344 are in clinical stage I. Although some ATR inhibitors have been reported, no ATR inhibitors have yet been marketed, and there remains a need in the art for new ATR inhibitors, particularly those having high activity and other superior properties.
The invention comprises the following steps:
the invention aims to provide a novel fused pyrimidine derivative and application thereof.
In order to achieve the above purpose, the invention adopts the technical scheme that:
a fused pyrimidine derivative is a compound shown in a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, said heterocyclic group optionally being substituted with 1-3R's, which may be the same or different 3 Optionally substituted with 1-2 oxo groups;
R 3 is H, cyano, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (halo) C 1 -C 6 ) Alkoxy, carboxyl, (C1-C6) alkoxycarbonyl, carbamoyl which is unsubstituted or substituted by 1-2 (C1-C6) alkyl;
a is unsubstituted or substituted by 1 to 3 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C6-C10) aryl, 5-10 membered heteroaryl;
n is 1, 2 or 3;
y is-C (O) -, -S (O) 2 -、-S(O)-、-C(S)-、-CH 2 -、-C(O)CH 2 -、-CH 2 C(O)-；
L is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (C) 2 -C 6 ) Alkenyl group (C) 3 -C 6 ) Cycloalkyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl, -NR 5 R 6 ；
R 5 、R 6 The same or different are each independently selected from hydrogen, (C) 1 -C 6 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, said heterocyclic group optionally being substituted with 1-2 oxo groups;
R 4 ，R 7 is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) Alkyl acyl group (C) 1 -C 6 ) Alkoxycarbonyl, (C) 1 -C 6 ) Alkylamido group (C) 1 -C 6 ) Alkylsulfinyl, (C) 1 -C 6 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 6 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 6 ) Alkyl groupSubstituted carbamoyl;
the aryl is phenyl or naphthyl; heteroaryl is a monocyclic or polycyclic unsaturated cyclic system containing one or more heteroatoms, wherein the cyclic system is aromatic and is imidazolyl, pyrazolyl, pyridinyl, indolyl, azaindolyl, benzimidazolyl, benzopyrazolyl, indolonyl, isoindolonyl, pyrazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzoxazolyl; heterocyclyl is a saturated or partially saturated monocyclic, polycyclic, bridged or spiro ring system containing one or more heteroatoms, wherein the ring system is pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, indolinyl or thiazolinyl.
Preferably, the derivative is a compound of formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-3 heteroatoms, said heterocyclic group optionally being substituted with 1-2R's, which may be the same or different 3 Substituted or substituted with 1-2 oxo groups;
R 3 is H, cyano, halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, carboxyl, (C) 1 -C 4 ) Alkoxycarbonyl, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group;
a is unsubstituted or substituted by 1-2 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
n is 1 or 2;
y is-C (O) -, -S (O) 2 -、-C(O)CH 2 -、-CH 2 C(O)-；
L is unsubstituted or substituted 1-3 identical or different R' s 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, (C) 2 -C 4 ) Alkenyl group (C) 3 -C 6 ) Cycloalkyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl, -NR 5 R 6 ；
R 5 、R 6 The same or different are each independently selected from hydrogen, (C) 1 -C 4 ) Alkyl, (C) 3 -C 4 ) Cycloalkyl, 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-6 membered heteroaryl;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, said heterocyclic group optionally being substituted with 1-2 oxo groups;
R 4 ，R 7 Is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
Still more preferably, the derivative is a compound represented by the general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-2 heteroatoms, said heterocyclic group optionally being substituted with 1-2R's, which may be the same or different 3 Substituted or substituted with 1-2 oxo groups;
R 3 is H, cyano, halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, carboxyl, (C) 1 -C 4 ) Alkoxycarbonyl, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group;
a is unsubstituted or substituted by 1-2 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
n is 1 or 2;
y is-C (O) -, -S (O) 2 -、-C(O)CH 2 -、-CH 2 C(O)-；
L is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, 5-10 membered heteroaryl, -NR 5 R 6 ；
R 4 ，R 7 Is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
Further preferably, the derivative is a compound shown in a general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic ring containing at least 1-2 heteroatomsA radical, said heterocyclyl optionally being substituted with 1 to 2 identical or different R' s 3 Substituted or substituted with 1-2 oxo groups;
R 3 is H, cyano, halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, carboxyl, (C) 1 -C 4 ) Alkoxycarbonyl, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group;
a is unsubstituted or substituted by 1-2 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
n is 1 or 2;
y is-C (O) -, -S (O) 2 -、-C(O)CH 2 -、-CH 2 C(O)-；
L is (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, 5-10 membered heteroaryl, and the aforementioned L may also optionally be substituted with 1-3R's, which may be the same or different 7 Substitution;
R 4 ，R 7 is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
More preferably, the derivative is a compound shown in a general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached, form the structure:
a is unsubstituted or substituted by 1-2 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
n is 1 or 2;
y is-C (O) -;
l is (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, 5-10 membered heteroaryl, and the aforementioned L may also optionally be substituted with 1-3R's, which may be the same or different 7 Substitution;
R 4 ，R 7 is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
Still more preferably, the compounds of formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached, form the structure:
a is And A is optionally substituted with 1 to 3R's, which may be the same or different 4 And (3) substitution.
n is 1 or 2;
y is-C (O) -;
l is (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, 5-10 membered heteroaryl, and the aforementioned L may also optionally be substituted with 1-3R's, which may be the same or different 7 Substitution;
R 4 ，R 7 is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
Still further preferred are compounds of formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein R is 1 And R is 2 Together with the nitrogen atom to which they are attached
n is 1 or 2;
y is-C (O) -;
l is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, thienyl, pyrrolyl, pyrazolyl, furyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, benzothiazolyl, benzoxazolyl;
a is And A is optionally substituted with 1 to 3R's, which may be the same or different 4 And (3) substitution.
R 4 ，R 7 Is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
The compounds of the general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof are particularly preferred in the present invention, as obtained in examples 1-80 below.
Most particularly preferred in the context of the present invention are compounds of the general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-isopropyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-cyclopropylcarbonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-propionyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-cyclobutylformyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3-methoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-methoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3, 4-dimethoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (1, 3-benzodioxol-5-yl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-difluoromethoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-acetylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3-acetylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-methylsulfonyl 4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-isopropylformyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-propionyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-benzoyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (2-acryloyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (3-fluorobenzoyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (3, 4-dimethoxybenzoyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6-cyclopropylcarbonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6-benzoyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (7-methyl-1H-indol-4-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (7-methyl-1H-indol-4-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (3 a,7 a-dihydro-1H-benzo [ d ] imidazol-1-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (3 a,7 a-dihydro-1H-benzo [ d ] imidazol-1-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indazol-4-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-3-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine.
Pharmaceutically acceptable salts of the compounds of formula I above are salts with acids selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid.
The invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
The "halogen" in the substituent means fluorine, chlorine or bromine; "alkyl" refers to a straight or branched chain alkyl group; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkoxy" refers to straight or branched chain alkoxy; "alkenyl" refers to straight or branched chain alkenyl groups; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to phenyl or naphthyl that is unsubstituted or substituted; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, indolyl, azaindolyl, benzimidazolyl, benzopyrazolyl, indolonyl, isoindolonyl, pyrazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to a monocyclic, polycyclic, bridged or spiro ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, indolinyl, imidazolidinyl, thiazolinyl, and the like.
A pharmaceutical composition comprising a compound of formula I, and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, in admixture with a pharmaceutically acceptable carrier.
Use of a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, or a composition comprising a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of ATR mediated diseases.
Such preparation is useful for the treatment and/or prevention of ATR mediated diseases including, but not limited to, osteosarcoma, glioblastoma, lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer, non-small cell lung cancer, pancreatic cancer, biliary tract cancer, bladder cancer, colorectal cancer, breast cancer, ovarian cancer, multiple myeloma, skin cancer, melanoma, leukemia, or renal cancer.
The invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
The invention also includes pharmaceutical compositions comprising as active ingredient a compound of formula I and pharmaceutically acceptable salts and/or solvates thereof, together with a pharmaceutically acceptable carrier; the compounds of the invention may also be used in combination with other active ingredients, provided that they do not produce other adverse effects, such as allergic reactions.
The carriers used in the pharmaceutical compositions of the present invention are of the usual types available in the pharmaceutical arts, including binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigment-free, flavoring agents and the like, which are available for oral formulations; a pH regulator, an osmotic pressure regulator, a solubilizer, a stabilizer, etc. for injectable preparations; matrices, diluents, lubricants, preservatives, and the like, which may be used in topical formulations. Pharmaceutical formulations may be administered orally, parenterally (e.g., intravenously, subcutaneously, intraperitoneally, etc.), or topically (e.g., ocular, nasal, sublingual, dermal, etc.), and if some drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The precise amount of the compounds of the present invention to treat cancer, particularly diseases caused by ATR abnormalities, will vary from subject to subject, depending on the type of subject, the age and general condition, the severity of the disease being treated, the particular compound used, and the mode of administration, e.g., route and frequency of administration, etc. One of ordinary skill in the art can determine the appropriate effective amount using only routine experimentation.
The amount of the compound administered may be from about 0.1 to 160mg/kg body weight per day, preferably 1 to 60mg/kg body weight per day. It will be appreciated that the dosage may vary depending on the patient's needs, the disease caused by the abnormality of ATR being treated and the particular compound being used. Moreover, it will be appreciated that the initial dose administered may be increased beyond an upper limit in order to rapidly reach the desired blood level, or the initial dose may be less than optimal, and the daily dose may be gradually increased during treatment, depending on the particular situation. If desired, the daily dose may also be divided into multiple doses, for example 2-4 times per day.
Mammal means a human or an animal.
The amount of active ingredient, i.e. the compound according to the invention, in the pharmaceutical composition and unit dosage forms thereof may vary depending on the particular application, the potency of the particular compound and the desired concentration. Generally, the content of active ingredient will be between 0.5% and 90% by total weight of the composition.
In combination therapy, the compound of the invention and the other compound may be administered simultaneously or separately, and in the case of simultaneous administration, the compound of the invention and the other compound may be combined in a single pharmaceutical composition or in separate compositions.
The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods of preparing the same. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final compounds of the present invention are prepared by methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these synthetic routes are as defined below or as defined in the claims.
In the compounds of the general formula I according to the invention, in the first to fourth routes, the following compounds are exemplified, and the substituents R1, R2 and Y, L are as defined above.
In the first route, 2-amino isobutyric acid is used as a starting material, intermediate 1 is obtained through esterification, intermediate 2 is obtained through substitution reaction of intermediate 1 and 3-bromopropionic acid ethyl ester, intermediate 3 is obtained through nucleophilic substitution of intermediate 2 and bromobenzyl, intermediate 4 is obtained through Claisen ester condensation of intermediate 3 under the action of sodium ethoxide, intermediate 5 is obtained through cyclization of intermediate 4 and urea at high temperature, intermediate 6 is obtained through chlorination, intermediate 7 is obtained through nucleophilic substitution reaction of intermediate 6 and R1R2 substituted amine, intermediate 9 is obtained through Suzuki coupling and debenzylation of intermediate 7 and different substituted boric acid esters, and I-I is obtained through reaction of intermediate 9 and alkyl or aromatic halide, alkyl or aromatic acyl chloride, alkyl or aromatic sulfonyl chloride.
In the second route, 4-aminobutyric acid is taken as a starting material, intermediate 10 is obtained through esterification, intermediate 10 and ethyl 2-bromoisobutyrate are subjected to substitution reaction to obtain intermediate 11, then intermediate 12 is obtained through nucleophilic substitution reaction with bromobenzyl, intermediate 12 is condensed with Claisen ester under the action of sodium ethoxide to obtain intermediate 13, then intermediate 14 is obtained through cyclization with urea under the action of sodium methoxide, intermediate 15 is obtained through chlorination reaction of intermediate 14, and intermediate 15 and R 1 R 2 The substituted amine is subjected to nucleophilic substitution reaction to obtain an intermediate 16, the intermediate 16 and different substituted boric acid esters are subjected to Suzuki coupling to obtain an intermediate 17, the intermediate 17 is debenzylated under the action of palladium hydroxide/carbon to obtain an intermediate 18, and then the intermediate 18 is reacted with alkyl or aromatic halide, alkyl or aromatic chlorine, alkyl or aromatic sulfonyl chloride to obtain I-ii.
In the second route, intermediate 19 is taken as a raw material, and debenzylation is carried out under the action of chloroformate-1-chloroethyl to obtain intermediate 20, intermediate 20 reacts with different substituted aliphatic or aromatic acyl chlorides and different substituted aliphatic or aromatic sulfonyl chlorides to obtain intermediate 21, and intermediate 20 reacts with different substituted boric acid esters to obtain I-iii.
In the fourth route, 19 is used as a raw material, intermediate 22 is obtained through Suzuki coupling, intermediate 22 is debenzylated under the action of palladium hydroxide/carbon to obtain intermediate 23, and intermediate 23 reacts with different substituted active esters to obtain I-iv.
The compound containing the condensed pyrimidine skeleton has novel structure and excellent property, and the obtained compound can be used as an ATR inhibitor, and the in vitro kinase activity screening shows that the compound has obvious inhibiting activity on ATR.
The specific embodiment is as follows:
in the examples below, the methods of preparing some of the compounds are depicted. It will be appreciated that the following methods, as well as other methods known to those of ordinary skill in the art, may be applicable to the preparation of all compounds described herein. The examples are intended to illustrate, but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-600, and the mass spectrum is measured by a Waters ACQUITY triple four-stage liquid chromatography-mass spectrometer; the reagents used are analytically pure or chemically pure.
Example 1 (R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine
1.1 Synthesis of ethyl 2-amino-2-methylpropionate hydrochloride (1)
40g (488.9 mmol) of 2-amino-2-methylpropanoic acid was added to 400mL of absolute ethanol in an ice bath, 69.1g (580 mmol) of thionyl chloride was added dropwise to the reaction mixture, and the reaction mixture was heated to 80℃and reacted for 10 hours. After the reaction, the reaction mixture was concentrated to obtain 65g of a white solid, with a yield of 97%. Without further purification, it was used directly in the next reaction. MS (ESI) m/z 132.0[ M+H ] ] + 。
1.2 Synthesis of ethyl 3- (2, 2-dimethyl-3-ethoxy-3-oxo) -aminopropionate (2)
25g (149 mmol) of ethyl 2-amino-2-methylpropionate hydrochloride, 32.38g (178.9 mmol) of ethyl 3-bromopropionate, 96g (695.6 mmol) of DIPEA and 24g (144.5 mmol) of KI were added to acetonitrile in this order, and reacted at 80℃for 96 hours. After the reaction, the reaction solution was cooled to room temperature, suction-filtered, and the filtrate was concentrated to give 22g of brown oil in a yield of 65%, which was used directly in the next step without further purification.
1.3 Synthesis of ethyl 3- (1-benzyl-2, 2-dimethyl-3-ethoxy-3-oxo) -aminopropionate (3)
34g (147.0 mmol) of intermediate 2 is added into 20mL of DMF under ice bath, 3.6g (150 mmol) of NaH is slowly added into the reaction solution, the temperature is controlled to be 0-3 ℃, stirring is carried out for 30min, 30g (175.4 mmol) of bromobenzyl is slowly added into the reaction solution in a dropwise manner, and the reaction is carried out for 24h at room temperature after the dropwise addition. After the reaction, the reaction mixture was poured into water and extracted with EtOAc (50 mL. Times.3). The organic layer was washed with 120mL of saturated brine, dried, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give 23.6g of a colorless oil in 50% yield. MS (ESI) m/z 322.2[ M+H ] +.
1.4 Synthesis of 1-benzyl-2, 2-dimethyl-4-carboxylic acid ethyl ester-3-oxo-pyrrolidine (4)
20g (62.2 mmol) of intermediate 3 and 8.5g (126 mmol) of sodium ethoxide were added successively to 130mL of dry toluene at room temperature, and the temperature was raised to 85℃for reaction for 8h. After the reaction, the reaction solution was concentrated, and the residue was poured into water and extracted with DCM (50 ml×3). The organic layer was washed with 120mL of saturated brine, dried, filtered and concentrated in vacuo to give 10.27g of a brown oil in 60% yield, which was used in the next step without further purification. MS (ESI) m/z 276.2[ M+H ]] + 。
1.5 Synthesis of 6-benzyl-7, 7-dimethyl-6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine-2, 4 (3H) -dione ((5)
20g (72.6 mmol) of intermediate 4, 17.46g (290.7 mmol) of urea are added in succession to the flask and reacted for 8h at 180 ℃. After the reaction is finished, 50mL of water is added into the reaction liquid after the reaction liquid is slightly cooled, the filtration is carried out, and 13.2g of pale yellow solid is obtained after the filter cake is dried, and the yield is 67%. MS (ESI) m/z 269.9[ M-H ]] - 。
1.6 6-benzyl-2, 4-dichloro-7, 7-dimethyl-6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine (6)
10g (36.9 mmol) of intermediate 5 was slowly added to 150mL POCl under ice-bath 3 In the middle, reflux overnight under nitrogen atmosphere. After the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was poured into ice water, the pH was adjusted to 8-9, extracted with methylene chloride (30 mL. Times.3), the organic layers were combined, washed with 30mL of saturated brine, dried, filtered off with suction, and the filtrate was concentrated, and the residue was purified by column chromatography to give 4.5g of pale yellow solid with a yield of 40%.
1.7 Synthesis of (R) -7, 7-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -6-benzyl-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine (7)
5g (16.2 mmol) of intermediate 6, 1.8g (17.8 mmol) of (R) -3-methylmorpholine and 6.29g (48.6 mmol) of DIPEA were added in succession to 10mL of DMF at room temperature and reacted for 8h at 50 ℃. After the reaction, the reaction mixture was cooled to room temperature, poured into 10mL of water, extracted with ethyl acetate (20 mL. Times.3), and the organic phase was concentrated to give a pale yellow oil, which was purified by column chromatography to give 4.2g of pale yellow solid with a yield of 70%. MS (ESI), m/z 373.1[ M+H ]] + 。
1.8 Synthesis of (R) -7, 7-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl ] -6-benzyl-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine (8)
2.24g (6 mmol) of intermediate 7, 2.19g (9 mmol) of 4-indoleboronic acid pinacol ester were added to 15mL of absolute ethanol at room temperature, degassed three times, 0.21g (0.3 mmol) of ditriphenylphosphine palladium dichloride was added, degassed three times, 5mL (3.8 g,17.9 mmol) of aqueous potassium phosphate solution was added at 70℃and reacted for 16h at 75℃after the addition, the organic phase was concentrated, 10mL of water was added to the residue, extracted with dichloromethane (10 mL. Times.3), the organic phase was concentrated, and column chromatography was purified to give an off-white solid, 2.1g, yield 78%. MS (ESI), m/z 454.1[ M+H ] ] + ，452.0[M-H] - 。
1.9 Synthesis of (R) -7, 7-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine (9)
1.5g (3.3 mmol) of intermediate 8 are reacted at room temperature,0.75g of palladium hydroxide/carbon is added into 20mL of absolute ethyl alcohol in sequence, the reaction is carried out for 24 hours at 60 ℃ under the hydrogen atmosphere, after the reaction is finished, the reaction liquid is filtered by diatomite, and the filtrate is concentrated to obtain 0.99g of off-white solid with the yield of 80 percent. MS (ESI), m/z 364.0[ M+H ]] + ,362.1[M-H] - 。
1.10 Synthesis of (R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine (Compound of example 1)
0.08g (0.2 mmol) of intermediate 9 and 0.04g (0.3 mmol) of triethylamine are sequentially added into 3mL of dry dichloromethane at room temperature, 0.042g (0.3 mmol) of methanesulfonyl chloride is slowly dripped into the reaction liquid in an ice bath, and the reaction is carried out for 2h at room temperature after the dripping. After the reaction, 5mL of water was added to the reaction mixture, which was extracted with methylene chloride (10 mL. Times.3), and the organic phase was concentrated and purified by column chromatography to give a white solid in 60% yield.
The compounds of examples 2 to 20 were synthesized using alkyl or aromatic acid chloride according to the synthesis method of example 1, the structures and melting points of examples 1 to 20, MS, 1 The H-NMR data are shown in Table 1.
Table 1 examples 1 to 20
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Example 21 (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-methylsulfonyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
21.1 Synthesis of ethyl 4-aminobutyrate hydrochloride
40g (488.9 mmol) of 4-aminobutyric acid was added to 400mL of absolute ethanol in ice bath, 80g (672.4 mmol) of thionyl chloride was slowly added dropwise, and the mixture was reacted at 80℃for 15 hours. After the reaction, the reaction mixture was concentrated to obtain 68g of a white solid, and the yield was 95%. Without further purification, it was used directly in the next reaction. MS (ESI) m/z 132.1[ M+H ]] + 。
21.2 Synthesis of ethyl 4- (2, 2-dimethyl-3-ethoxy-3-oxo) aminobutyrate
18.14g (118.1 mmol) of ethyl 4-aminobutyrate hydrochloride, 27.62g (141.6 mmol) of ethyl 2-bromo-2-methylpropionate, 65g (470.3 mmol) of potassium carbonate and 19.5g (117.5 mmol) of potassium iodide were successively added to 50mL of DMF and reacted at 100℃for 72 hours at room temperature. The reaction solution was cooled to room temperature, a large amount of white solid was precipitated, insoluble matter was removed by suction filtration, and was used directly in the next step without further purification. MS (ESI) m/z 246.1[ M+H ]] + 。
21.3 Synthesis of ethyl 4- (1-benzyl-2, 2-dimethyl-3-ethoxy-3-oxo) aminobutyrate
Under ice bath, 27.3g (125.6 mmol) of ethyl 4- (2, 2-dimethyl-3-ethoxy-3-oxo) aminobutyrate was added to 20mL of DMF, 3.6g (150 mmol) of NaH was slowly added to the reaction solution, the temperature was controlled to 0-3 ℃, stirring was carried out for 30min, 24g (140.3 mmol) of bromobenzyl was slowly added dropwise to the reaction solution, the reaction was completed at room temperature for 24h, and after the reaction was completed, the reaction solution was poured into 50mL of water and extracted with EtOAc (60 mL. Times.3). The organic layer was washed with saturated brine (2X 20 mL), dried, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 23.5g of a colorless oil in 50% yield. MS (ESI) m/z 322.2[ M+H ] ] + 。
21.4 Synthesis of 1-benzyl-2, 2-dimethyl-4-carboxylic acid ethyl ester-3-oxo piperidine
20g (59.6 mmol) of ethyl 4- (1-benzyl-2, 2-dimethyl-3-ethoxy-3-oxo) aminobutyrate and 7.69g (113 mmol) of sodium ethoxide were added successively to 130mL of dry toluene at room temperature, and the mixture was heated to 85℃for reaction. After the reaction, 30mL of water was added to the reaction mixture, extracted with methylene chloride (3X 40 mL), the organic layers were combined, washed with saturated brine (2X 20 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was evaporated to dryness to give 11.53g of a brown oil in 74% yield, which was used directly in the next reaction without further purification.
21.5 Synthesis of 7-benzyl-8, 8-dimethyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine-2, 4 (1H, 3H) -dione
3.4g (147.8 mmol) of finely divided metallic sodium are added to 140mL of absolute ethanol under ice bath and stirred. After the metal sodium was completely consumed, 13.5g (224.7 mmol) of urea and 14.7g (56.2 mmol) of ethyl 1-benzyl-2, 2-dimethyl-4-carboxylate-3-oxopiperidine were added to the reaction solution, and heated under reflux for 24 hours. After the reaction, the reaction solution was cooled to room temperature. The reaction solution was concentrated under reduced pressure, the residue was poured into ice water, the pH was adjusted to 6-7 with acetic acid under ice bath, filtration was performed, the cake was washed with ice water, and the cake was the product, which was dried to give 9.6g of brown solid with a yield of 60%. MS (ESI) m/z 286.1[ M+H ] ] + 。
21.6 Synthesis of 7-benzyl-2, 4-dichloro-8, 8-dimethyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
10g (35.1 mmol) of 7-benzyl-8, 8-dimethyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] are placed in an ice bath]Pyrimidine-2, 4 (1H, 3H) -dione was slowly added to 200mL POCl 3 In the middle, reflux overnight under nitrogen atmosphere. After the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was poured into ice water, the pH was adjusted to 8-9, dichloromethane (40 mL. Times.3) was extracted, the organic layers were combined, washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, suction-filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography to give 7.8g of pale yellow solid with a yield of 70%. MS (ESI) m/z 322.1[ M+H ]] + 。
21.7 Synthesis of (R) -8, 8-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -7-benzyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
To 1.93g (6 mmol) of 7-benzyl-2, 4-dichloro-8, 8-dimethyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] at room temperature]To a solution of pyrimidine in DMF was added 0.67g (6.6 mmol) (R) -3-methylmorpholine and 2.3g (17.8 mmol) DIPEA. The reaction mixture was stirred at 50℃for 5h. After the reaction, the reaction mixture was cooled to room temperature, the residue was poured into ice water, ethyl acetate (10 ml×3) was extracted, the organic layers were combined, washed with saturated brine (5 ml×3), dried over anhydrous sodium sulfate, suction-filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography to give 1.58g of pale yellow solid with a yield of 68%. MS (ESI), m/z 373.1[ M+H ] ] + ； 1 H NMR(600MHz,DMSO-d 6 )δ7.39(d,J＝7.1Hz,2H),7.33(t,J＝7.6Hz,2H),7.24(t,J＝7.3Hz,1H),4.08(q,J＝6.4Hz,1H),3.80(dd,J＝11.3,1.8Hz,1H),3.71(d,J＝14.1Hz,1H),3.62(d,J＝14.1Hz,1H),3.59–3.56(m,2H),3.55(s,1H),3.47(td,J＝11.5,2.6Hz,1H),3.34(dd,J＝11.2,2.6Hz,1H),2.50–2.47(m,2H),2.46–2.43(m,2H),1.43(d,J＝14.3Hz,6H),1.21(d,J＝6.7Hz,3H)。
21.8 Synthesis of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl) -7-benzyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
1.7g (4.3 mmol) of (R) -8, 8-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -7-benzyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] are reacted successively at room temperature]Pyrimidine, 1.6g (6.5 mmol) 4-indoleboronic acid pinacol ester were added to 15mL absolute ethanol, degassed three times, 0.15g (0.2 mmol) bis triphenylphosphine palladium dichloride was added, degassed three times, 5mL (2.8 g,13.2 mmol) aqueous potassium phosphate was added at 70℃and reacted at 75℃for 16h, the reaction was completed, the organic phase was concentrated, 5mL water was added to the residue, extracted with dichloromethane (20 mL. Times.3), the organic phase was concentrated, and column chromatography was performed to give 1.4g of an off-white solid with a yield of 79%. M.p, 124.6-128.7 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.24(s,1H),8.14(d,J＝7.4Hz,1H),7.52(d,J＝7.9Hz,1H),7.45(dd,J＝10.8,5.5Hz,4H),7.35(t,J＝7.5Hz,2H),7.26(t,J＝7.3Hz,1H),7.20(t,J＝7.7Hz,1H),4.05(d,J＝6.3Hz,1H),3.86(dd,J＝12.3,7.3Hz,2H),3.71(dd,J＝10.9,2.0Hz,1H),3.63(dd,J＝13.3,8.1Hz,2H),3.58(d,J＝11.7Hz,1H),3.52(d,J＝13.3Hz,1H),3.46(dd,J＝17.4,6.6Hz,1H),2.61–2.53(m,4H),1.64(s,3H),1.58(s,3H),1.23(d,J＝6.5Hz,3H)。
21.9 (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Synthesis of pyrimidine 1.5g (3.2 mmol) of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl) -7-benzyl-5, 6,7, 8-tetrahydropyrido [3,4-d ] are taken at room temperature]Pyrimidine and 0.15g palladium hydroxide/carbon are added into 20mL absolute ethyl alcohol in sequence, the reaction is carried out for 24 hours at 60 ℃ under the hydrogen atmosphere, after the reaction is finished, the reaction liquid is filtered through diatomite, and the filtrate is concentrated to obtain 0.84g of off-white solid with the yield of 70 percent. M.p, 99.7-102.9 ℃; MS (ESI), m/z 378.3[ M+H ] ] + ； 1 H NMR(600MHz,DMSO-d 6 )δ11.25(s,1H),8.15–8.06(m,1H),7.51(dd,J＝7.3,4.6Hz,1H),7.45(d,J＝1.9Hz,1H),7.41(s,1H),7.24–7.14(m,1H),4.03(d,J＝2.1Hz,1H),3.89(d,J＝10.5Hz,1H),3.75(d,J＝10.9Hz,1H),3.62(d,J＝11.1Hz,2H),3.46(d,J＝2.1Hz,1H),3.01–2.91(m,2H),2.76(s,2H),2.65(d,J＝3.0Hz,2H),1.52(dd,J＝15.4,3.7Hz,6H),1.23(d,J＝5.6Hz,3H)。
21.10 Synthesis of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-methylsulfonyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (example 21)
0.08g (0.2 mmol) of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine and 0.04g (0.3 mmol) of triethylamine are added to 3mL of dry dichloromethane in sequence at room temperature, 0.042g (0.3 mmol) of methanesulfonyl chloride is slowly dripped into the reaction liquid under ice bath, and the reaction is carried out for 2H at room temperature. After the reaction, 5mL of water was added to the reaction mixture, which was extracted with methylene chloride (20 mL. Times.3), and the organic phase was concentrated, and purified by column chromatography to give 0.05g of a white solid in 60% yield.
The compounds of examples 22 to 43 were synthesized according to the synthesis method of example 21 using alkyl or aromatic acid chlorides, the structures, chemical names and melting points of examples 21 to 43, MS, 1 The H-NMR data are shown in Table 2.
Table 2 examples 21 to 43
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Example 44 (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (2-dimethylaminoacetyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
44.1 Synthesis of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (2-chloroacetyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
0.2g (0.5 mmol) of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine and 0.11g (1.1 mmol) of triethylamine are added to 3mL of dry dichloromethane in sequence at room temperature, 0.120g (1.1 mmol) of chloroacetyl chloride is slowly dripped into the reaction liquid under ice bath, and the dripping is completed, and the reaction is carried out at room temperature for 2H. After the reaction, 5mL of water was added to the reaction mixture, the mixture was extracted with methylene chloride (10 mL. Times.3), and the organic phase was concentrated, and purified by column chromatography to give 0.19g of a gray solid in 66% yield.
44.2 Synthesis of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (2-dimethylaminoacetyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (example 44)
0.1g (0.22 mmol) of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (2-chloroacetyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine, 0.026g (0.32 mmol) of dimethylamine hydrochloride, 0.12g (0.86 mmol) of potassium carbonate were added to 3mL of acetonitrile at room temperature and reacted at 60℃for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, the reaction mixture was concentrated, 5mL of water was added to the reaction mixture, the mixture was extracted with methylene chloride (10 mL. Times.3), and the organic phase was concentrated and purified by column chromatography to give 0.079g of a white solid in 79% yield.
44.3 Synthesis of (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- [2- (4-methylpiperazin-1-yl) acetyl ] -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (example 45)
N-methylpiperazine is used as a raw material, and (R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- [2- (4-methylpiperazin-1-yl) acetyl ] -4- (3-methylmorpholine-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine is synthesized according to a synthesis method of 44.2. The yield thereof was found to be 77%.
Examples 44 to 45 were structured, chemical name, melting point, MS, 1 The H-NMR data are shown in Table 3.
TABLE 3 examples 44 to 45
Synthesis of (R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -4- (3-methylmorpholin-4-yl) using 7-aza-4-indoleboronic acid ester as starting material according to the Synthesis method of 1.1.8 in example 1]-6-benzyl-5, 7-dihydro-6H-pyrrolo [3,4-d]Pyrimidine or (R) -8, 8-dimethyl-2- (1H-7-azaindol-4-yl) -4- (3-methylmorpholin-4-yl) -7-benzyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine. (R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -4- (3-methylmorpholin-4-yl) -5, 7-dihydro-6H-pyrrolo [3,4-d ] was then synthesized according to the method of synthesis 1.1.9 in example 1]Pyrimidine or (R) -8, 8-dimethyl-2- (1H-7-azaindol-4-yl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] ]Pyrimidine was synthesized by the method of 1.10 in example 1 using alkyl or aromatic acid chloride to give the compounds of examples 46 to 57, in factExamples 46 to 57 were structured, chemical name, melting point, MS, 1 The H-NMR data are shown in Table 4.
Table 4 examples 46 to 57
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Example 58 (R) -7, 7-dimethyl-2- (1H-indol-2-one-4-yl) -6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine
58.1 Synthesis of (R) -7, 7-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine
1g (2.7 mmol) of (R) -7, 7-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -6-benzyl-5, 7-dihydro-6H-pyrrolo [3,4-d ] are taken up at room temperature]Pyrimidine was added to 10mL of methylene chloride, 1.5g (10.5 mmol) of 1-chloroethyl chloroformate was added dropwise under ice bath, and after completion of the dropwise addition, the mixture was reacted at room temperature for 10 hours, the solvent was evaporated, 10mL of methanol was added to the residue, and the reaction was refluxed for 3 hours. After the reaction, the solvent was evaporated to dryness, the residue was pH-adjusted to 7-8 with 1N NaOH solution, extracted with methylene chloride (10 mL. Times.3), dried, filtered off with suction, and the filtrate was concentrated to give 0.3g of a pale yellow oil in 40% yield. . MS (ESI) m/z 283.12[ M+H ]] + 。
58.2 Synthesis of (R) -7, 7-dimethyl-2-chloro-6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine
(R) -7, 7-dimethyl-2-chloro-6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine was synthesized in the same manner as the synthesis method of 1.10 in example 1, starting from propionyl chloride and (R) -7, 7-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine.
58.3 Synthesis of (R) -7, 7-dimethyl-2- (1H-indol-2-one-4-yl) -6-benzoyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine
With (R) -7, 7-dimethyl-2-chloro-6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidine and 4-boronic acid ester-indol-2-one starting materials were synthesized (R) -7, 7-dimethyl-2- (1H-indol-2-one-4-yl) -6-benzoyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] according to the synthesis method of 1.8 in example 1]Pyrimidine. The yield thereof was found to be 56%. MS (ESI) m/z 437.0[ M+H ]] + 。
The compounds of examples 59 to 65 were synthesized using (R) -7, 7-dimethyl-2-chloro-6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine and the different substituted borates as starting materials, using 58.3 synthesis methods, and using (R) -7, 7-dimethyl-2-chloro-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine and m-methylsulfonyl benzoyl chloride or p-sulfonylbenzoyl chloride as starting materials to give the corresponding intermediates according to 57.2 synthesis methods, followed by reaction with the different substituted borates or the different substituted amines as starting materials. The structure, chemical name and MS data of examples 58-75 are shown in table 5.
Table 5 examples 58 to 75
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The compounds of examples 76 to 80 were synthesized by the synthesis method of example 1 using various substituted small molecular amines and intermediate 6 as raw materials, the structures, chemical names and melting points of examples 76 to 80, MS, 1 The H-NMR data are shown in Table 6.
TABLE 6 examples 76 to 80
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The ATR enzyme activity of the compound of the present invention was studied, and the results were as follows
The fused pyrimidine compounds of the formula I are prepared by performing in vitro ATR enzyme activity test on the fused pyrimidine compounds of the formula I according to the invention by using a fluorescence assay method, wherein the following compounds are prepared by the above examples.
The kinase buffer consists of 50mM HEPES (pH 7.5), 0.0015% Brij-35, 1M MnCl 2 Composition is prepared. Stop buffer consisted of 100mM HEPES (pH 7.5), 0.015% Brij-35, 0.2%Coating Reagent#3, 50mM EDTA. The compound was diluted with 100% dimethyl sulfoxide to 1000/3 times the final desired maximum inhibitor concentration. To two wells, 100 μl of dimethyl sulfoxide was added, and the compound-free control and enzyme-free control were performed in the same 96-well plate. This plate is denoted as source plate. Transfer 40 μl of compound from the source plate to a new 384 well plate as an intermediate plate, transfer 60nL of compound to the assay plate by Echo in 100% dimethyl sulfoxide. 2 parts of an enzyme solution was prepared, and kinase was added to the kinase base buffer. Transfer 2 times enzyme solution to assay plate, 3 To each well of the 84-well assay plate, 10. Mu.L of enzyme solution was added. Incubate at room temperature for 10min. FAM-labeled peptide and ATP were added to kinase base buffer, peptide solution was transferred to assay plates, and 10 μl of peptide solution was added to each well of 384-well assay plates. The kinase reaction was stopped, the transformation data was copied from the Caliper program, and drug IC was obtained by the Bliss method 50 Values. ATR enzyme IC of some examples 50 The activity data are shown in Table 7.
TABLE 7 ATR enzyme IC of the examples section 50 Activity data
Examples IC 50 (nM)
Example 3 7.6
Example 4 8.2
Example 7 7.2
Example 9 4.0
Example 10 3.0
Example 11 7.0
Example 13 4.7
Example 14 4.2
Example 15 3.8
Example 16 3.0
Example 17 5.0
Example 19 5.8
Example 20 4.3
Example 24 8.0
Example 25 8.7
Example 28 8.9
Example 29 9.4
Example 31 6.1
Example 40 4.7
Example 41 9.4
Example 43 9.1
Example 48 6.6
AZ20 4.8
From the above table, it is described that the compounds of the general formula have good ATR inhibitory activity, and that some of the compounds are equivalent or superior to the positive control AZ20.
Further experiments were then performed to inhibit the activity of LOVO cells and HT-29 cells in vitro on the partially fused pyrimidine derivatives of formula I above according to the invention.
Human colon cancer HT-29 and LOVO cells were purchased from the Shanghai cell Bank (CAS) of the national academy of sciences. Cells were recovered and passaged 2-3 times for stabilization, and cells in the logarithmic growth phase were collected, prepared into single cell suspensions and counted, and the cell concentration was adjusted to the desired concentration, and 100 μl per well was added to a 96-well cell culture plate. 100. Mu.L of complete medium of test compound or positive control compound or complete medium of control (2 wells per concentration) was added per well and incubated in an incubator for 72 h. The fluorescence intensity (530/590 nm) of each well was measured using the Alamar blue method, and proliferation rates at each concentration were calculated.
Proliferation rate = 1- [ (negative control well-test well)/(negative control well-positive control well) ×100% ]
The results of the experiments on LOVO cells L and HT-29 for some of the compounds are shown in Table 8.
Table 8 cell proliferation Rate (%)
Cell activity test results of the compounds show that the activity of part of the compounds on LOVO and HT-29 cells is equivalent to or better than that of the positive control AZ20.
Meanwhile, in vitro kinase and cell activity test results show that the compound has good ATR enzyme activity and excellent cell activity, and part of the compound activity is better than that of a positive control medicine AZ20.

Claims (11)

1. A fused pyrimidine derivative, characterized in that: the derivative is a compound shown in a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, said heterocyclic group optionally being substituted with 1-3R's, which may be the same or different 3 Optionally substituted with 1-2 oxo groups;
R 3 is H, cyano, halogen, (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkoxy, carboxyl, (C) 1 -C 6 ) Alkoxycarbonyl, unsubstituted or substituted by 1 to 2 (C) 1 -C 6 ) An alkyl-substituted carbamoyl group;
a is unsubstituted or substituted by 1 to 3 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
n is 1, 2 or 3;
y is-C (O) -, -S (O) 2 -、-S(O)-、-C(S)-、-CH 2 -、-C(O)CH 2 -、-CH 2 C(O)-；
L is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (C) 2 -C 6 ) Alkenyl group (C) 3 -C 6 ) Cycloalkyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl, -NR 5 R 6 ；
R 5 、R 6 The same or different are each independently selected from hydrogen, (C) 1 -C 6 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, said heterocyclic group optionally being substituted with 1-2 oxo groups;
R 4 ，R 7 is halogen, hydroxy, nitro, cyano, carboxyl, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) Alkyl acyl group (C) 1 -C 6 ) Alkoxycarbonyl, (C) 1 -C 6 ) Alkylamido group (C) 1 -C 6 ) Alkylsulfinyl, (C) 1 -C 6 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 6 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 6 ) An alkyl-substituted carbamoyl group;
the aryl is phenyl or naphthyl; heteroaryl is a monocyclic or polycyclic, unsaturated cyclic system containing one or more heteroatoms; heterocyclyl is a monocyclic, multicyclic, bridged or spiro ring system containing one or more heteroatoms.
2. A fused pyrimidine derivative as claimed in claim 1, wherein: the derivative is a compound of a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-3 heteroatoms, said heterocyclic group optionally being substituted with 1-2R's, which may be the same or different 3 Substituted or substituted with 1-2 oxo groups;
R 3 is H, cyano, halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, carboxyl, (C) 1 -C 4 ) Alkoxycarbonyl, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group;
a is unsubstituted or substituted by 1-2 identical or different R 4 Substituted 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl;
n is 1 or 2;
y is-C (O) -, -S (O) 2 -、-C(O)CH 2 -、-CH 2 C(O)-；
L is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, (C) 2 -C 4 ) Alkenyl group (C) 3 -C 6 ) Cycloalkyl, (C) 6 -C 10 ) Aryl, 5-10 membered heteroaryl, -NR 5 R 6 ；
R 5 、R 6 The same or different are each independently selected from hydrogen, (C) 1 -C 4 ) Alkyl, (C) 3 -C 4 ) Cycloalkyl, 4-10 membered heterocyclyl, (C) 6 -C 10 ) Aryl, 5-6 membered heteroaryl;
Or R is 5 And R is 6 Together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, said heterocyclic group optionally being substituted with 1-2 oxo groups;
R 4 ，R 7 is halogen, hydroxy or nitroCyano, carboxyl, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, halo (C) 1 -C 4 ) Alkyl, halo (C) 1 -C 4 ) Alkoxy, (C) 1 -C 4 ) Alkyl acyl group (C) 1 -C 4 ) Alkoxycarbonyl, (C) 1 -C 4 ) Alkylamido group (C) 1 -C 4 ) Alkylsulfinyl, (C) 1 -C 4 ) Alkylsulfonyl, (C) 1 -C 3 ) Alkylene dioxy, unsubstituted or substituted by 1 to 2 (C) 1 -C 4 ) Amino substituted by alkyl, unsubstituted or substituted by 1-2 (C 1 -C 4 ) An alkyl-substituted carbamoyl group.
3. A fused pyrimidine derivative as claimed in claim 2, wherein: the derivative is a compound shown in a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
wherein,
R 1 and R is 2 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-2 heteroatoms, said heterocyclic group optionally being substituted with 1-2R's, which may be the same or different 3 Substituted or substituted with 1-2 oxo groups;
l is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, 5-10 membered heteroaryl, -NR 5 R 6 。
4. A fused pyrimidine derivative as claimed in claim 3, wherein: the derivative is a compound shown in a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
Wherein,
l is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, 5-10 membered heteroaryl.
5. The fused pyrimidine derivative as claimed in claim 4, wherein: the derivative is a compound shown in a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
wherein,
y is-C (O) -;
R 1 and R is 2 Together with the nitrogen atom to which they are attached, form the structure:
6. the fused pyrimidine derivative as claimed in claim 5, wherein: the derivative is a compound shown in a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
wherein,
a is Or A as described above is optionally substituted with 1 to 3R's, which may be the same or different 4 And (3) substitution.
7. The novel fused pyrimidine derivatives as claimed in claim 6, wherein: the derivative is a compound shown in a general formula I, and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
R 1 and R is 2 Together with the nitrogen atom to which they are attached
L is unsubstituted or substituted by 1 to 3 identical or different R 7 Substituted (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl, phenyl, thienyl, pyrrolyl, pyrazolyl, furyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, benzothiazolyl, benzoxazolyl;
A is And A is optionally substituted with 1 to 3R's, which may be the same or different 4 And (3) substitution.
8. The novel fused pyrimidine derivatives as claimed in claim 7, wherein: the derivative is a compound of a general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-acetyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-isopropyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-cyclopropylcarbonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-propionyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6-cyclobutylformyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3-methoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-methoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3, 4-dimethoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (1, 3-benzodioxol-5-yl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbonyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-difluoromethoxybenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (4-acetylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-4-yl) -6- (3-acetylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-methylsulfonyl 4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-isopropylformyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-propionyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7-benzoyl-4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (2-acryloyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (3-fluorobenzoyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -8, 8-dimethyl-2- (1H-indol-4-yl) -7- (3, 4-dimethoxybenzoyl) -4- (3-methylmorpholin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6-methanesulfonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6-cyclopropylcarbonyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6-benzoyl-4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-7-azaindol-4-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (7-methyl-1H-indol-4-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (7-methyl-1H-indol-4-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (3 a,7 a-dihydro-1H-benzo [ d ] imidazol-1-yl) -6- (3-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (3 a,7 a-dihydro-1H-benzo [ d ] imidazol-1-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indazol-4-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine;
(R) -7, 7-dimethyl-2- (1H-indol-3-yl) -6- (4-methylsulfonylbenzoyl) -4- (3-methylmorpholin-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine.
9. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 8, and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, in admixture with a pharmaceutically acceptable carrier.
10. Use according to claim 1 or 9, characterized in that: the application of the compound of the general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof or the composition containing the compound of the general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicines for treating and/or preventing ATR-mediated diseases.
11. The use according to claim 10, wherein: the prevention of ATR mediated disease is osteosarcoma, glioblastoma, lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer, non-small cell lung cancer, pancreatic cancer, biliary tract cancer, bladder cancer, colorectal cancer, breast cancer, ovarian cancer, multiple myeloma, skin cancer, melanoma, leukemia, or renal cancer.
CN202210578200.XA 2022-05-25 2022-05-25 Fused pyrimidine derivative and application thereof Pending CN117164590A (en)

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